The overall goal for this 5-year research project is to explore the ramifications of our initial discovery: Neurotransmitter-receptor stimulation influences processing of the amyloid beta-protein precursor (APP). The proposed experiments all revolve around this common theme and are designed to clarify mechanisms of APP processing. In order to accomplish this goal, we will conduct experiments using cell culture and brain slice systems. There are 4 specific aims. In aim #1, we will determine the effects of receptor activation on APP metabolism and synthesis. Individual experiments will explore the effects of receptor activation on APP endosomal-lysosomal processing, APP cleavage, APP gene expression, and translation rates; whether receptor activation also changes the secretion of other transmembrane proteins such as APLP1, APLP2, and TGF-alpha; and whether receptor-mediated APP secretion protects cells from excitotoxic damage. In aim #2, we will determine whether receptor stimulation blocks Abeta secretion. We will also determine whether receptor stimulation blocks the abnormally high Abeta secretion caused by the APP mutations in the Swedish FAD kindred, and whether other FAD- associated APP mutations suppress receptor-activated APP processing. In aim #3m we will explore additional cell surface receptors for their effects on APP processing and we will examine receptor chimeras to characterize the signal transduction pathways that mediate APP processing. In aim #4, we will examine receptor-mediated regulation of APP processing in mammalian brain. Using an in vitro rat brain slice preparation, we will study the conditions in which neuronal activity influences APP processing in brain as opposed to cell cultures. In particular, we will determine which specific neurotransmitter receptor systems mediate APP cleavage and secretion of soluble Abeta in mammalian brain. These experiments rely upon expertise that we have developed over the past 3 years and extend our initial observations regarding the effects of neurotransmitter receptor activation on APP processing. Successful achievement of these 4 specific aims will delineate mechanisms of APP processing and identify sites for potential therapeutic intervention at which APP metabolism may be altered.